STK4 (also known as MST1) is a serine-threonine kinase that is part of the Hippo signaling pathway. STK4 is involved in multiple cellular processes including proliferation, trafficking, apoptosis, immune response and stress response (Cottini, F., et al., Nat. Med., 20 (6), 599-606 (2014); Salojin, K. V., et al., PLoS One, 9(5), e98151 (2014); Ardestani, A., et al., Nat. Med., 20 (4), 385-397, (2014)). STK4 reactivates the Hippo mediator YAP1 thereby triggering apoptosis in hematologic malignancies characterized by high levels of DNA damage. DNA double-strand break (DSB) followed by activation of DNA damage response in cancers occurs in premalignant and malignant conditions. However, progression to malignancy is prevented in precancerous settings by senescence and apoptotic responses until the tumor suppressor TP53 (p53) is inactivated, thereby triggering genomic instability and enhancing tumor cell growth.
Recently, it has been shown that hematologic malignancies, including multiple myeloma, lymphoma, and leukemia, contain pervasive DNA damage that leads to activation of a p53-independent proapoptotic network centered on relocalization of ABL1 kinase. Unlike normal cells in which ABL1 kinase triggers cell death with the Hippo pathway co-activator YAP1, low levels of YAP1 in hematologic malignancies prevent nuclear ABL1-induced apoptosis (Cottini, F., et al., Nat. Med., 20 (6), 599-606, (2014)).
Downregulation of STK4 with specific shRNAs has been shown to lead to a robust increase of YAP1 protein levels compared to scrambled shRNA. Inactivation of serine-threonine kinase 4 (STK4) has also been shown to restore YAP1 levels triggering cell death in vitro and in vivo demonstrating that YAP1 is under the control of STK4. Inhibition of STK4 with small molecule inhibitors has the potential to be a treatment for cancers and other disorders. Known STK4 inhibitors have demonstrated poor kinase selectivity, cell penetration and pharmacokinetic properties. For these reasons, there remains a need for novel and potent small molecule STK4 inhibitors.